The emerging link between O-GlcNAcylation and neurological disorders

Ma, Xiaofeng; He, Lijun; He, Yating; Hao, Junwei

doi:10.1007/s00018-017-2542-9

Cited by 56 publications

(39 citation statements)

References 207 publications

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“…Although much less studied, evidence is also emerging for O-GlcNAcylation's roles in Parkinson's disease (305,317). As stated above, OGT maps to the Parkinson dystonia locus at Xq13 (329).…”

Section: Asbmb Award Article: Regulation Of Signaling and Transcriptionmentioning

confidence: 97%

Nutrient regulation of signaling and transcription

Hart

2019

Journal of Biological Chemistry

288

225

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O‐GlcNAc cycles on and off thousands of nucleocytoplasmic proteins and has extensive crosstalk with protein phosphorylation. O‐GlcNAc cycles on nearly all proteins involved in transcription, where it regulates gene expression in response to nutrients. O‐GlcNAc also regulates the cycling of the TATA‐binding (TBP) protein on and off DNA during the transcription cycle. Targeted, inducible, deletion of the O‐GlcNAc Transferase (OGT) in aCAMKII positive (excitatory) neurons of adult mice results in a morbidly obese mouse with a satiety defect. Thus, O‐GlcNAcylation not only serves as a nutrient sensor in all cells, but also is directly involved in appetite regulation. O‐GlcNAcylation also plays an important role in the trafficking of the AMPA receptors in neurons and in the development of functional synaptic spines. Recent studies have shown that more than one‐half of all human protein kinases are modified by O‐GlcNAc and all kinases that have been tested are indeed regulated in some way by the sugar. Abnormal O‐GlcNAcylation of CAMKII contributes directly to diabetic cardiomyopathy and to arrhythmias associated with diabetes. Prolonged elevation of O‐GlcNAc, as occurs in diabetes, contributes directly to diabetic complications and is a major mechanism of glucose toxicity. Drugs that elevate O‐GlcNAcylation in the brain, which, in‐turn, prevents hyperphosphorylation, appear to be of benefit for the treatment of Alzheimer's disease in animal models. To date, all cancers have elevated O‐GlcNAc cycling, which may play a key role in the regulation of metabolism in cancer cells. Support or Funding Information Supported by NIH P01HL107153, R01GM116891, R01DK61671, and N01‐HV‐00240. Dr. Hart receives a share of royalty received by the university on sales of the CTD 110.6 antibody, which are managed by JHU. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Section: Asbmb Award Article: Regulation Of Signaling and Transcriptionmentioning

confidence: 97%

Nutrient regulation of signaling and transcription

Hart

2019

Journal of Biological Chemistry

288

225

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“…Moreover, protein O-GlcNAcylation is very sensitive to the availability of uridine diphospho-N-acetylglucosamine, the GlcNAc donor for O-GlcNAcylation [43] and downstream metabolite of glucose, hence O-GlcNAcylation is often referred to as a nutrient sensor in cells [20, 43,44]. Loss of O-GlcNAcylation was shown to result in loss of cellular function or even cell death [45] and the disturbance of normal O-GlcNAc function has been linked to many diseases, including Alzheimer's disease, diabetes, and other chronic illnesses [46,47]. Therefore, the proper functioning of O-GlcNAcylation in cells is essential, however, how this regulation is fine-tuned is still not well understood.…”

Section: Regulation Of O-glcnacylationmentioning

confidence: 99%

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

2018

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A wide variety of protein post-translational modifications (PTMs) decorate cellular proteins, regulating their structure, interactions and ultimately their function. The density of co-occurring PTMs on proteins can be very high, where multiple PTMs can positively or negatively influence each other's actions, termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, whereby we focus on crosstalk between protein phosphorylation and O-GlcNAcylation. These two PTMs largely target identical (i.e., Ser and Thr) amino acids in proteins. Phosphorylation/O-GlcNAcylation crosstalk comes in many flavors, for instance by competition for the same site/residue (reciprocal crosstalk), as well as by modifications influencing each other in proximity or even distal on the protein sequence. PTM crosstalk is observed on the writers of these modifications (i.e., kinases and O-GlcNAc transferase), on the erasers (i.e., phosphatases and O-GlcNAcase), and on the readers and the substrates. We describe examples of all these different flavors of crosstalk, and additionally the methods that are emerging to better investigate in particular phosphorylation/O-GlcNAcylation crosstalk.

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“…Recent work proposes the dynamic form of intracellular protein glycosylation, O-linked N-Acetylglucosamine (O-GlcNAc), as an attractive target for regulating aging-specific synaptic and plasticity-related molecular alterations, as well as neurodegenerative phenotypes [6][7][8][9][10][11]. O-GlcNAcylation is regulated by two enzymes-O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA)-which catalyze the addition and removal of O-GlcNAc to serine and threonine residues of proteins, respectively.…”

Section: Introductionmentioning

confidence: 99%

Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

et al. 2019

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Mounting evidence in animal models indicates potential for rejuvenation of cellular and cognitive functions in the aging brain. However, the ability to utilize this potential is predicated on identifying molecular targets that reverse the effects of aging in vulnerable regions of the brain, such as the hippocampus. The dynamic post-translational modification O-linked N-Acetylglucosamine (O-GlcNAc) has emerged as an attractive target for regulating aging-specific synaptic alterations as well as neurodegeneration. While speculation exists about the role of O-GlcNAc in neurodegenerative conditions, such as Alzheimer's disease, its role in physiological brain aging remains largely unexplored. Here, we report that countering age-related decreased O-GlcNAc transferase (OGT) expression and O-GlcNAcylation ameliorates cognitive impairments in aged mice. Mimicking an aged condition in young adults by abrogating OGT, using a temporally controlled neuron-specific conditional knockout mouse model, recapitulated cellular and cognitive features of brain aging. Conversely, overexpressing OGT in mature hippocampal neurons using a viral-mediated approach enhanced associative fear memory in young adult mice. Excitingly, in aged mice overexpressing neuronal OGT in the aged hippocampus rescued in part age-related impairments in spatial learning and memory as well as associative fear memory. Our data identify O-GlcNAcylaton as a key molecular mediator promoting cognitive rejuvenation.

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The emerging link between O-GlcNAcylation and neurological disorders

Cited by 56 publications

References 207 publications

Nutrient regulation of signaling and transcription

Nutrient regulation of signaling and transcription

Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

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